C.—Determination of the Lethal Doses of Venom for Different Species of Animals.
It is very difficult to specify, even within broad limits, the dose of venom necessary to kill a human being. The quantity of poison introduced by the bite of a venomous snake depends, as has already been stated, upon a large number of factors, and, very fortunately, this quantity is not always sufficient to cause death. Thus in India, that is to say in the region in which snakes are most numerous and most dangerous, the mean mortality seems scarcely to exceed 35 to 40 per cent., so far as it is possible to judge from official statistics. But, by experimenting upon animals, and commencing with known doses of venom, which has first been dried and then dissolved again in always the same quantity of physiological saline solution or sterile distilled water, we can determine exactly, for each kind of venom, and for each species of animal, the minimum lethal dose per kilogramme of animal.
The entire series of data collected by investigators who have devoted themselves to this study may be summed up as follows:—
Minimal doses lethal in twenty-four hours for a guinea-pig weighing from 600 to 700 grammes:—
| Colubridæ. | |||
|---|---|---|---|
| Venom of | Naja tripudians | 0·0002 | gramme |
| “ | Bungarus cæruleus | 0·0006 | “ |
| “ | Naja haje | 0·003 | “ |
| VIPERIDÆ. | |||
|---|---|---|---|
| Venom of | Vipera berus | 0·04 | gramme |
| “ | Vipera russellii (Daboia) | 0·001 | “ |
| “ | Lachesis lanceolatus | 0·02 | “ |
| “ | Lachesis mutus (Surucucu) | 0·02 | “ |
| “ | Lachesis neuwiedii (Urutù) | 0·02 | “ |
| “ | Lachesis flavoviridis | 0·007 | “ |
| “ | Ancistrodon contortrix | 0·015 | “ |
Cobra-venom. Dose lethal in twenty-four hours for different animals:—
| Dog | 0·0008 | gramme per | kilogramme | |
| Rabbit | 0·0005 | “ | “ | |
| Guinea-pig | 0·0004 | “ | “ | |
| Rat | 0·0001 | “ | 150 | grammes |
| Mouse | 0·000003 | “ | 25 | “ |
| Frog | 0·0003 | “ | 30 | “ |
Venom of Bungarus cæruleus (Common Krait), according to Elliot, Sillar, and Carmichael.[15] Minimal lethal doses for:—
| Frog | 0·0005 | gramme | |
| Rat | 0·001 | “ | |
| Rabbit (by subcutaneous injection) | 0·00008 | “ | per kilogramme |
| Rabbit (by intravenous injection, according to G. Lamb) | 0·00004 | “ | “ |
Venom of Enhydrina valakadien (according to Elliot and Fraser).[16] Minimal lethal doses per kilogramme:—
| Rat | 0·00009 | gramme |
| Rabbit | 0·00006 | “ |
| Cat | 0·0002 | “ |
Venom of Enhydris curtus:—
Rat 0·0005 to 0·0006 gramme per kilogramme
Venom of Notechis scutatus (syn. Hoplocephalus curtus; the Tiger Snake of Australia):—
| Rabbit (by intravenous injection, according to Tidswell) | 0·00006 gramme per kilogramme |
Venom of Vipera russellii (Daboia):—
| Rabbit (by intravenous injection, according to G. Lamb) | 0·00005 gramme per kilogramme |
Venom of Lachesis gramineus (Green Pit-Viper, India):—
| Rabbit (by intravenous injection, according to G. Lamb) | 0·002 gramme per kilogramme |
Venom of Crotalus adamanteus (Californian Rattle-Snake):—
| Rabbit (by intravenous injection, according to McFarland, G. Lamb, and Flexner and Noguchi) | 0·00025 gramme per kilogramme |
It will have been seen from the foregoing figures, that the respective sensitiveness of the dog, cat, rabbit, guinea-pig, rat, mouse, and frog, with regard to the same venom, is in no way proportional to the weight of these animals.
The species mentioned are, per unit of weight, more or less resistant to intoxication; and, on experimenting with other animals, as for instance the monkey, pig, ass, and horse, we find that the monkey is much more susceptible to intoxication than the dog, and that the ass is extremely sensitive (0·010 gramme of Cobra-venom is sufficient to kill it), while the horse is less so, and the pig is by far the most resistant.
The same weight of dry Cobra-venom, let us say 1 gramme to be precise, will enable us to kill 1,250 kilogrammes of dog, 2,000 kilogrammes of rabbit, 2,500 kilogrammes of guinea-pig, 1,430 kilogrammes of rat, or 8,333 kilogrammes of mouse.
The lethal dose for a horse being, as I have ascertained by my own experiments, about 0·025 gramme, 1 gramme of dry Cobra-venom will therefore suffice to kill 20,000 kilogrammes of horse.
Assuming that man, in proportion to his weight, possesses a resistance intermediate between that of the dog and that of the horse, we may consider that the lethal dose for a human being is about 0·015 gramme. It follows, therefore, that 1 gramme of venom would kill 10,000 kilogrammes of man, or, let us say, 165 persons of an average weight of 60 kilogrammes.
Another extremely important fact, which must not be lost sight of, is that differences of toxicity, which are often considerable, are exhibited by the venoms of different specimens of the same species of snake, or by the venom of the same snake collected at different times. I have found, for instance, in the case of the specimens of Naja and Lachesis reared in my laboratory, that, according to the length of time that the animals had been without food, and to the nearness or otherwise of the moulting period, the venom was more or less active, and that on evaporation it left behind a more or less considerable quantity of dry extract. In certain cases, immediately after the moult and after a prolonged fast, the venom was ten times more active than after a plentiful meal or before the moult.
The figures given above must therefore not be regarded as determining the minimal lethal doses of the different venoms, except in a purely comparative way, and they must be considered only as data useful to know when it is desired to experiment upon animals with these substances.
Variations of this kind are observed in the case of all species of snakes. Thus Phisalix rightly insists upon the necessity of always noting, besides the species of snake, the place of origin and the season; for he has himself seen that, as regards French vipers, those of the Jura, for example, produce in the spring a venom almost devoid of local phlogogenic action; while vipers from the vicinity of Clermont-Ferrand, though less toxic, produce much more serious local effects.
On the other hand, it has been shown by Th. Madsen and H. Noguchi, in a very interesting study of venoms and anti-venoms,[17] that, when we examine the relation between dose and toxicity, we find that the interval separating the moment of inoculation from that of death diminishes only up to a certain point in proportion as the dose is increased. In the case of the guinea-pig, with 0·0005 gramme of Cobra-venom the interval is 3 hours 75 seconds; but after this, an increase in the dose produces only a relatively inconsiderable acceleration of death. There is therefore no strict ratio between the dose inoculated and the time that elapses until death supervenes.